ABSTRACT The possible role of pesticides in the etiology of breast cancer remains largely unresolved and continues to be a cause of serious concern in the general public. This is due in part to important limitations and/or the narrow focus of previous epidemiologic studies. The long-term goal of the proposed study is to identify the cancer risks associated with individual pesticides in order to better inform public policy and individual decision-making. The objective of this application is to identify any elevated risk of breast cancer associated with individual pesticides among a cohort of highly exposed women, specifically spouses in the NIH-administered Agricultural Health Study cohort, a well-characterized, prospective, multi-state cohort that includes approximately 51,000 male farmers and 32,000 wives. This is an excellent population in which to address this objective because of its large size, high rate of follow-up, and availability of detailed pesticide use, occupational, demographic, lifestyle, physical activity, dietary, and reproductive history information collected from both the farmers and their wives at enrollment in the mid-1990s and again in a 5-year follow-up interview. Importantly, several of the most commonly used pesticides in this cohort are or were widely used by the general public. The central hypothesis is that pesticides implicated as mammary carcinogens in animals or in vitro or previously linked to breast cancer in epidemiologic studies will be associated with breast cancer risk in such a highly exposed population of women. This hypothesis will be tested via two specific aims: 1) Identify any increased risk of malignant breast cancer associated with use of specific pesticides;and 2) Identify any increased risk of malignant breast cancer related to sources of non-specific pesticide exposure often found in agricultural communities. Under the first aim, breast cancer risk will be examined in relation to use of individual pesticides. Use by the woman and her husband will be considered separately to account for differences in the nature and extent of resulting exposure. Under the second aim, breast cancer risk will be investigated in relation to factors that increase opportunity for exposure to pesticides generally, including consumption of potentially contaminated well water, washing of clothes worn during pesticide application, and storage of pesticides in or near the home. Analyses will be based on the 31,531 women with no history of cancer at enrollment, with an estimated 805 incident cases of breast cancer identified through 2006 via population-based cancer registries. Relative risks will be estimated using data from both interviews (pre-diagnostic only), via Cox proportional hazards models including the full cohort, as well as separately by menopausal status and state of residence. Potential confounders, including demographic, lifestyle, dietary, and reproductive factors, will be accounted for. The proposed study offers an unusual opportunity to investigate, in a cost- and time-efficient manner, the effects of individual pesticides on breast cancer risk. This research is significant because it is expected to advance our understanding of the role of individual pesticides in the etiology of breast cancer and to do so in a methodologically rigorous manner not previously possible. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This area of research has potentially important public health implications, given the ubiquity of exposure to pesticides through diet, occupation, residential use, and other routes. Animal studies and very limited epidemiologic research suggest that certain commonly used pesticides may be risk factors for breast cancer. However, this risk in humans remains unknown or highly uncertain. The proposed study will help address these important gaps in our knowledge and help to inform the debate among policy makers and individuals concerning the risks and benefits of these chemicals.